The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal fibrosing lung disease with limited approved treatment options. The bioactive lysophospholipid lysophosphatidic acid (LPA) and the LPA1 receptor have been implicated in the etiology and pathogenesis of IPF, positioning LPA1 as a promising therapeutic target for IPF and other fibrotic diseases. The LPA1 antagonist BMS-986020 600 mg BID was efficacious in a 6-month placebo-controlled Phase 2 clinical trial in IPF patients by slowing lung function decline as measured by rate of decline of forced vital capacity (FVC) (CHEST, 154, p1061–69, 2018). BMS-986278 is a novel next generation LPA1 antagonist currently in Phase I clinical trials. BMS-986278 is a potent and complete antagonist of LPA action at LPA1-mediated Gi, Gq, G12, and β-arrestin signaling pathways in both cells heterologously expressing human LPA1 and in primary human lung fibroblasts. In vivo, BMS-986278: 1) inhibits LPA-stimulated histamine release in mice; 2) demonstrates antifibrotic activity, as shown by decreases in picrosirius red staining area of the lung in the chronic rodent bleomycin model. BMS-986278 demonstrates excellent pharmacokinetics in preclinical species: 1) oral bioavailability = 70% (mouse); 100% (rat); 79% (monkey) and 2) clearance (mL/min/kg) = 37 (mouse); 15 (rat); 2 (monkey). BMS-986278 has negligible activity at bile acid and other clinically relevant drug transporters (BSEP, MDR3 IC50 = >100 μM; OATP1B1 IC50 = 35.5 μM). BMS-986278 represents a novel promising LPA1 antagonist for the treatment of multiple fibrotic diseases.